Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Carcinoma

Adenocarcinoma

Carcinoma, Squamous Cell

Carcinoma, Adenosquamous

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Cisplatin

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive cisplatin IV over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo extended beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.

External Beam Radiation Therapy

Internal Radiation Therapy

Laboratory Biomarker Analysis

Jyoti S Mayadev

This phase I trial studies the side effects and best dose of ipilimumab when given after chemoradiation therapy in treating patients with stages IB2-IIB or IIIB-IVA cervical cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as ipilimumab, may find tumor cells and help carry tumor-killing substances to them. Giving ipilimumab together with chemoradiation therapy may be a better way treat cervical cancer.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of adjuvant ipilimumab following concurrent weekly cisplatin and extended field radiation in women with newly diagnosed locally advanced cervical cancer stage IB2/ IIA with-positive para-aortic lymph nodes only and stage IIB/IIIB/IVA with positive lymph nodes.

II. To determine the feasibility of the treatment regimen over the four cycles of adjuvant ipilimumab once the MTD is estimated.

III. To assess the toxicities of the treatment regimen per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

SECONDARY OBJECTIVES:

I. To examine progression free survival for 1 year after study completion. II. To determine site of recurrence, loco-regional versus distant, for one year after completion of therapy.

III. To estimate the frequency of chronic toxicities experienced within one year after completion of therapy.

TERTIARY OBJECTIVES:

I. To enumerate the human papillomavirus (HPV)-subtype-specific T-cells and characterize the kinetics of HPV-subtype-specific T-cell expansion associated with chemoradiation and ipilimumab treatment.

II. To characterize the association between differential expression of immune markers on leukocytes from human leukocyte antigen (HLA)-A\*0201 patients and response to chemoradiation and ipilimumab treatment.

III. To assess qualitative changes in maximum standardized uptake value (SUVmax) from positron emission tomography (PET)/computed tomography (CT) after treatment with chemoradiation and ipilimumab.

IV. To bank residual plasma (obtained from leukocyte processing) for future research.

OUTLINE: This is a dose-escalation study of ipilimumab.

Patients receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 15, 22, 29, and 36, undergo external beam radiation therapy 5 days a week for 6 weeks, and then undergo intracavitary brachytherapy for approximately 2 weeks. Within 2 weeks, patients receive ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 1 year.

Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA Cervical Cancer

A Phase I Trial of Sequential Ipilimumab After Chemoradiation for the Primary Treatment of Patients With Locally Advanced Cervical Cancer Stages IB2/IIA With Positive Para-Aortic Lymph Nodes Only and Stage IIB/IIIB/IVA With Positive Lymph Nodes

Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical.

Summary statistics (and graphs) of translational research endpoints will be done by dose level. Relationships of these endpoints to response and PFS will be explored if practical. Within-patient changes in the FDG-PET/CT SUVmax and MTV (if available) will be examined.

Relationships of translational research endpoints to response will be explored if practical.

Will be summarized using Kaplan-Meier plots. Relationships of translational research endpoints to PFS will be explored if practical.

Will be summarized using Kaplan-Meier plots.

NRG Oncology

National Cancer Institute (NCI)

Symptoms and General Pathology

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Vaginal Neoplasms

Carcinoma, Endometrioid

Vaginal Diseases

Endometrial Neoplasms

Ovarian Neoplasms

Ovarian Diseases

Adnexal Diseases

Gonadal Disorders

Endocrine System Diseases

Vaginal Cancer

Ovarian Cancer

Adavosertib

Enzyme Inhibitors

Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Stephanie Lheureux

This phase I trial studies the side effects and best dose of adavosertib when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. External beam radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving adavosertib, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.

PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) and safety profile of adavosertib (AZD1775) in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

SECONDARY OBJECTIVES:

I. To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin.

II. To evaluate the pharmacodynamic effects of AZD1775 when administered in combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients treated in an expansion cohort at the RP2D).

III. To obtain preliminary information about the progression-free survival, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or clinical progression, of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.

OUTLINE: This is a dose-escalation study of adavosertib.

Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib orally (PO) on days 1, 3, and 5 or once daily (QD) on days 1-5 and cisplatin intravenously (IV) over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 4 months for 2 years.

Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers

A Phase I Study of the Wee 1 Kinase (Wee 1) Inhibitor AZD1775 in Combination With Radiotherapy and Cisplatin in Cervical, Upper Vaginal and Uterine Cancers (10041848, 10008224, 10008238, 10046888, 10014735)

To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Through regular investigator assessment, regular laboratory testing, etc. Frequency and severity of adverse events were tabulated using counts and proportions.

Patients undergo external beam radiation therapy (45-50Gy) on days 1-5, receive 100mg AZD1775 PO on days 1, 3, and 5, and receive 40 mg/m2 cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1

Patients undergo external beam radiation therapy (45-50Gy) on days 1-5, receive 100mg AZD1775 PO on days 3 and 5, and receive 40 mg/m2 cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

0-Normal activity. Fully active, able to carry on all pre-disease performance w/o restriction. 1-Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory \& able to carry out work of a light/sedentary nature. 2-In bed \<50% of the time. Ambulatory \& capable of all self-care, but unable to carry out any work activities. Up \& about \>50% of waking hours. 3-In bed \>50% of the time. Capable of only limited self-care, confined to bed/chair \>50% of waking hours. 4-100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed /chair. 5-Dead.

ECOG Performance Status

Primary Site

Prior Therapy

Describes the extent of cancer in the body. The extent increases with stage.

FIGO Stage

The grade of a cancer tells you how much the cancer cells look like normal cells. Lower grades look most like normal cells while higher grades look more abnormal.

Grade

Histology

The main limitation of our study is the small number of patients enrolled due to premature closure; yet the study showed the limiting toxicities of this triplet combination.

Dr. Stephanie Lheureux, PI

Patients undergo external beam radiation therapy on days 1-5, receive AZD1775 PO on days 1, 3, and 5, and receive cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Patients undergo external beam radiation therapy on days 1-5, receive AZD1775 PO on days 3 and 5, and receive cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Participants that were evaluable for response.

Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities

All Grade 1-2 Toxicities

Related Grade 1-2 Toxicities

All Grade 3-4 Toxicities

Related Grade 3-4 Toxicities

Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin

Not analyzed as samples were not collected, therefore no data are available.

Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin

4 Months Post Treatment

2 Years Post Treatment

Progression-free Survival

Overall Study

Patients receive cisplatin IV over 90 minutes on days 2, 9, 16, 23, 30, (and day 36 or 37 at the treating physician's discretion). Patients then undergo EBRT (either conventional RT or IMRT) QD 5 days a week for 25 fractions followed by LDR or HDR brachytherapy according to institution's standards. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients receive cisplatin and undergo EBRT followed by brachytherapy as in Arm I. Patients also receive triapine IV over 2 hours on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33. Treatment continues in the absence of disease progression or unacceptable toxicity.

Brachytherapy

Intensity-Modulated Radiation Therapy

Radiation Therapy

Triapine

Charles A Leath

This randomized phase III trial studies radiation therapy and cisplatin with triapine to see how well they work compared to the standard radiation therapy and cisplatin alone in treating patients with newly diagnosed stage IB2, II, or IIIB-IVA cervical cancer or stage II-IVA vaginal cancer. Radiation therapy uses high energy protons to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and cisplatin are more effective with triapine in treating cervical or vaginal cancer.

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of the experimental regimen of triapine (3AP), cisplatin, and radiation to increase overall survival relative to the standard/control regimen of cisplatin and radiation in women with uterine cervix or vaginal cancer.

SECONDARY OBJECTIVE:

I. To determine the relative progression-free survival impact of triapine-cisplatin radio-chemotherapy and cisplatin radio-chemotherapy.

TERTIARY OBJECTIVES:

I. To evaluate incidence and severity of hematologic and gastrointestinal (GI) adverse events by radiation modality; image guided intensity modulated radiation therapy (IG-IMRT) versus conventional pelvic radiotherapy. (05/30/2017) II. To summarize and compare differences in acute adverse events (Common Terminology Criteria for Adverse Events \[CTCAE\], version \[v\]4.0) by treatment arm and by radiation modality. (05/30/2017) III. To summarize and compare differences in chronic or late (\>= 30-days from off study treatment date) adverse events (CTCAE, v4.0) by treatment arm and by radiation modality. (05/30/2017) IV. To determine peripheral blood methemoglobin proportion before and after triapine infusion (optional for Arm 2 patients).

V. To explore whether knowledge-based planning (KBP) can improve IG-IMRT plans compared to plans that would have been delivered without KBP, estimate the resulting toxicity reduction using normal tissue complication probability (NTCP) models, and determine whether KBP should be a requirement for future IG-IMRT protocols.

VI. To determine the post-therapy 3-month fludeoxyglucose F-18 (18F-FDG) PET/CT metabolic complete response rate by treatment arm VII. To compare acute toxicity and chemotherapy delivery for atlas-based IG-IMRT vs. positron emission tomography (PET)/computed tomography (CT)-based IG-IMRT vs. conventional radiation therapy (RT), and assess the impact of treatment on changes in hematopoietic compensatory response.

VIII. To develop and validate machine learning and radiomics techniques for dose accumulation, automated treatment planning, and prediction of treatment response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 90 minutes on days 2, 9, 16, 23, 30, (and day 36 or 37 at the treating physician's discretion). Patients then undergo external beam radiation therapy (EBRT) (either conventional RT or intensity modulated radiation therapy \[IMRT\]) once daily (QD) 5 days a week for 25 fractions followed by low dose rate (LDR) or high dose rate (HDR) brachytherapy according to institution's standards. Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cisplatin and undergo EBRT followed by brachytherapy as in Arm I. Patients also receive triapine IV over 2 hours on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 2 years, and then every 6 months for 3 years.

The patient data from NCI #9434 will be merged with NRG-GY006 per the Protocol Analysis Plan.

Testing the Addition of a New Anti-Cancer Drug, Triapine, to the Usual Chemotherapy Treatment (Cisplatin) During Radiation Therapy for Advanced-stage Cervical and Vaginal Cancers

A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination With Intravenous Triapine in Women With Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer

Number of participants with hematologic toxicity during treatment period, where hematologic toxicity is defined as occurrence of any grade 3 or higher adverse events for neutropenia, leukopenia, lymphopenia, anemia, or thrombocytopenia. Adverse events are graded and categorized using CTCAE v4.0.

Number of participants with a maximum grade of 3 or higher that occurred during follow-up period. Adverse events are graded and categorized using CTCAE v4.0.

Peripheral blood methemoglobin collected at baseline and 1, 3, 5 and 24 hours after Triapine infusion on Day 1 in Arm II.

The assessment of metabolic complete response is based on the ratio of post 3-month therapy PET/CT maximum standardized update value (SUV) to pre-therapy PET/CT maximum SUV. The metabolic complete response is classified as complete response for a ratio of 0.33 or less, or partial response for a ratio between 0.34 and 0.75, or stable response for a ratio greater that 0.75 but less than 1.25, or progressive response for a ratio greater than 1.25.

Estimate for probability of overall survival at 3 years by Kaplan-Meier method, where overall survival is defined as the time from randomization to time of death due to any cause or the date of last contact, whichever occurs first.

Estimate for probability of progression free at 3 years by Kaplan-Meier method, where progression-free survival is defined as the time from randomization to the date of first documented disease recurrence/progression, death from any cause or date of last contact, whichever occurs first. Recurrence is defined as clinical, radiological or histological evidence of recurrent disease post study treatment. Disease progression will be determined from the physical examinations, which were conducted during treatment (day 9, 16, 23, 30 and 37) and follow-up (1 and 3 months after completing protocol therapy, every 3 months for years 1 and 2, and every 6 months for years 3, 4 and 5), and the PET/CT scan conducted 3 months after the end of treatment. Please note that progression defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1) is not required by the protocol.

Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v4.0.

All Adverse Events (AEs) occurring during treatment and up to 30 days after stopping the study treatment for participants who received any study treatment. Note that the population is different for all-cause mortality and adverse events. For all-cause mortality the population is "all eligible participants." For adverse event reporting, the population is "all patients who received any study treatment."

Patients receive cisplatin IV over 90 minutes on days 2, 9, 16, 23, 30, (and day 36 or 37 at the treating physician's discretion). Patients then undergo EBRT (either conventional RT or IMRT) QD 5 days a week for 25 fractions followed by LDR or HDR brachytherapy according to institution's standards. Treatment continues in the absence of disease progression or unacceptable toxicity.

Brachytherapy: Undergo brachytherapy

Cisplatin: Given IV

External Beam Radiation Therapy: Undergo EBRT

Intensity-Modulated Radiation Therapy: Undergo IMRT

Laboratory Biomarker Analysis: Correlative studies

Radiation Therapy: Undergo conventional RT

Arm I (Cisplatin, IMRT or RT, Brachytherapy)

Patients receive cisplatin and undergo EBRT followed by brachytherapy as in Arm I. Patients also receive triapine IV over 2 hours on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33. Treatment continues in the absence of disease progression or unacceptable toxicity.

Brachytherapy: Undergo brachytherapy

Cisplatin: Given IV

Intensity-Modulated Radiation Therapy: Undergo IMRT

Laboratory Biomarker Analysis: Correlative studies

Radiation Therapy: Undergo conventional RT

Triapine: Given IV

Arm II (Cisplatin, IMRT or RT, Brachytherapy, Triapine)

20-29 years

30-39 years

40-49 years

50-59 years

60-69 years

70-79 years

>= 80 years

Age, Customized

Christopher Purdy on behalf of Wei Deng, PhD

Overall Survival (OS) Rate at 3 Years

Progression-free Survival (PFS) Rate at 3 Years

Anemia

Other blood and lymphatic system disorders

White blood cell count decreased

Platelet count decreased

Neutrophil count decreased

Other investigations

Cardiac disorders

Eye disorders

Gastrointestinal disorders

General disorders

Hepatobiliary disorders

Infections and infestations

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

Neoplasms benign, malignant and unspecified

Nervous system disorders

Psychiatric disorders

Renal and urinary disorders

Reproductive system and breast disorders

Respiratory, thoracic and mediastinal disorders

Skin and subcutaneous tissue disorders

Surgical and medical procedures

Vascular disorders

Participants who received any study treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemoradiation Therapy and Ipilimumab in Treating Patients With Stages IB2-IIB or IIIB-IVA Cervical Cancer	NCT01711515	Cervical Adenoc... Cervical Adenos... Cervical Squamo... Stage IB2 Cervi... Stage II Cervic... Stage IIA Cervi... Stage IIB Cervi... Stage IIIB Cerv... Stage IVA Cervi...	Cisplatin External Beam R... Internal Radiat... Ipilimumab Laboratory Biom...	18 Years -	National Cancer Institute (NCI)
Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers	NCT03345784	Cervical Carcin... Endometrioid Ad... Malignant Femal... Recurrent Cervi... Stage I Uterine... Stage I Vaginal... Stage IA Uterin... Stage IB Cervic... Stage IB Uterin... Stage IB2 Cervi... Stage II Cervic... Stage II Uterin... Stage II Vagina... Stage IIA Cervi... Stage IIB Cervi... Stage III Cervi... Stage III Uteri... Stage III Vagin... Stage IIIA Cerv... Stage IIIA Uter... Stage IIIB Cerv... Stage IIIB Uter... Stage IIIC Uter... Vaginal Carcino...	Adavosertib Cisplatin External Beam R...	18 Years -	National Cancer Institute (NCI)
Testing the Addition of a New Anti-Cancer Drug, Triapine, to the Usual Chemotherapy Treatment (Cisplatin) During Radiation Therapy for Advanced-stage Cervical and Vaginal Cancers	NCT02466971	Advanced Vagina... Advanced Vagina... Advanced Vagina... Cervical Adenoc... Cervical Adenos... Cervical Squamo... Stage IB2 Cervi... Stage II Cervic... Stage II Vagina... Stage IIA Cervi... Stage IIB Cervi... Stage III Vagin... Stage IIIB Cerv... Stage IV Vagina... Stage IVA Cervi... Stage IVA Vagin... Unresectable Va... Vaginal Adenoca... Vaginal Adenosq... Vaginal Carcino... Vaginal Squamou...	Brachytherapy Cisplatin External Beam R... Intensity-Modul... Laboratory Biom... Radiation Thera... Triapine	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage ib2 cervical cancer ajcc v6 and v7